title: A comparison of the systemic toxicity of lidocaine versus its quaternary derivative QX-314 in mice.
abstract: OBJECTIVE
  We recently showed that the quaternary lidocaine derivative, QX-314, produces long-lasting local anesthesia with a slow onset in animal models in vivo. As quaternary agents do not rapidly penetrate biological membranes or the blood-brain barrier, QX-314 may represent a local anesthetic with decreased systemic toxicity compared with conventional tertiary aminoamines. To test this hypothesis, we conducted an in vivo animal study in mice to compare QX-314 with lidocaine in terms of its relative central nervous system (CNS) and cardiac toxicity.
  
  
  METHODS
  With approval from the institutional Animal Care Committee, we used the "up-and-down" method to determine the relative potencies (ED(50)) of lidocaine and QX-314 for CNS and cardiac toxicity in adult CD-1 mice (weight, 20 to 35 g). The animals were administered either intravenous lidocaine or QX-314 (dose range, 7.5 to 30 mg·kg(-1)) and were observed for signs of CNS toxicity (convulsions, ataxia, loss of righting reflex, and/or death). We also observed animals for electrocardiographic evidence of toxic effects on cardiac automaticity, conductivity, and rhythmicity.
  
  
  RESULTS
  The ED(50) of lidocaine for CNS toxicity as determined by the "up-and-down" method was 19.5 mg·kg(-1) (95% confidence interval [CI], 17.7 to 21.3 mg·kg(-1); n = 6) compared with 10.7 mg·kg(-1) for QX-314 (95% CI, 9.1 to 12.3 mg·kg(-1); n = 6) (potency ratio, 1.8). Similarly, the ED(50) of lidocaine for electrocardiographic evidence of cardiac toxicity was significantly higher than that of QX-314 (ED(50) of lidocaine, 21.2 mg·kg(-1); 95% CI, 19.0 to 23.4 mg·kg(-1); n = 6 vs ED(50) of QX-314, 10.6 mg·kg(-1); 95% CI, 8.4 to 12.8 mg·kg(-1); n = 6) (potency ratio, 2.0).
  
  
  CONCLUSIONS
  In this in vivo animal study, the relative potencies of QX-314 for systemic CNS and cardiac toxicity were significantly higher than those of lidocaine. These data do not support the hypothesis that QX-314 is a safer local anesthetic compared with lidocaine in terms of systemic toxicity. Whereas our results do not exclude the possibility that QX-314 may represent a clinically useful agent to produce long-lasting local anesthesia and nociceptive blockade after a single shot in humans, its systemic toxicity relative to conventional tertiary aminoamide local anesthetics and the underlying mechanisms warrant further study.
authors.affiliation: Department of Anesthesiology, Pharmacology & Therapeutics, Hugill Anesthesia Research Centre, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Helen M C
authors.initials: HM
authors.lastname: Cheung
authors.forename: Sang Mook
authors.initials: SM
authors.lastname: Lee
authors.forename: Bernard A
authors.initials: BA
authors.lastname: MacLeod
authors.forename: Craig R
authors.initials: CR
authors.lastname: Ries
authors.forename: Stephan K W
authors.initials: SK
authors.lastname: Schwarz
mesh_terms: D000779:Anesthetics, Local / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D002493:Central Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006331:Heart Diseases / Q000139:chemically induced* / Q000503:physiopathology; D007275:Injections, Intravenous; D008012:Lidocaine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D051379:Mice
chemical_list: D000779:Anesthetics, Local; C012647:QX-314; D008012:Lidocaine